4-halo derivatives of 2-hydroxymethylene delta4-androsten-17beta-ol-3-one and the corresponding 19-nor compounds



4-HALO DERIVATIVES F Z-HYDROXYMETHYL- ENE A -ANDROSTEN-17,6-0L-3-0NE ANDTHE CQRREEPONDING 19-NOR COMPOUNDS Howard J. Ringoldand GeorgeRosenkranz, Mexico City, Mexico, assignors to Syntex S.A., Mexico City,Mexico, a corporation of Mexico No Drawing. Filed Nov. 14, 1958, Ser.No. 773,829 Claims priority, application Mexico Nov. 18, 1957 17 Claims.(Cl. 260-3914) H mi:

In the above formula R represents hydrogen or a lower alkyl group suchas methyl, ethyl or propyl or a lower alkenyl group such as vinyl. Rrepresents hydrogen, a lower alkyl or benzyl group such as methyl,ethyl, propyl or benzyl, or a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms. The acyl group may be saturated or unsaturated,straight or branched chain aliphatic, cyclic or mixed cyclic-aliphaticand may be conventionally substituted with halogen or methoxy forexample. Typical acyl group are acetate, propionate, butyrate,hemisuccinate, enanthate, caproate, benzoate, trimethylacetate, ace:t-oxypropionate, cyclopentylpropionate, phenylpropionate or,B-chloropropionate. R represents hydrogen when R is alkyl or alkyleneand R represents hydrogen or a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms when R is hydrogen. X represents CH or hydrogen. Yrepresents chlorine or bromine.

The compounds above set forth are prepared by a process outlined in thefollowing equation:

esterflcatlon etheriflcation etc.

In the above equation R, R1, R X and Y represent the same groups asheretofore set forth.

In practicing the process above set forth 4-bromo or4-chloro-testosterone, c-1OW61 alkyl or lower alkenyl testosterone orthe same 19-nor compounds are reacted with ethyl formate in the presenceof sodium hydride to prepare the corresponding Z-hydroxymethylenederivatives. These compounds wherein R is hydrogen, When esterified withan acid chloride in aqueous alkaline solution (Schotten-BaumannReaction) were selectively esterified to give the corresponding2-acyloxymethylene compounds. Where the 17-hydroxy group is tertiary (Ris alkyl or alkenyl) the 2-acyloxymethylene compounds were obtained byconventional esterification with an acid anhydride in pyridine. Thesecondary hydroxyl group at C-17 was also further conventionallyesterified to give Z-acyloxymethylene 17-esters wherein the ester groupswere dilferent. The diesters of the compounds with a secondary C-l7hydroxy having the same ester groups were prepared by conventionalesterification with an excess of an acid anhydride. The ethers of thehydroxymethylene group were formed by reaction of the compounds with alower alkyl iodide or benzyl iodide and 17-esters of these othercompounds were formed by conventionally esterifying the ether compounds.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I A suspension of 10 g. of 4 chloro-testosterone in 500 cc. ofthiophene free anhydrous benzene was treated with 10 cc. of ethylformate and 3 g. of sodium hydride and the mixture was stirred undernitrogen for 5 hours at a temperature around 25 C. The precipitateconsisting of a mixture of thesodium salt of the Z-hydroxymethylenecompound and the excess of sodium hydride was collected by filtration,washed with benzene and dried. This mixture was slowly added to asolution of 20 cc. of concentrated hydrochloric acid and 500 cc. ofwater, under vigorous stirring; the stirring was continued for 30minutes and the precipitate was collected, abundantly washed withdistilled water, dried under vacuum and recrystallized fromacetone-hexane. There was thus obtained2-hydroxymethylene-4-chlorotestosterone.

Example II By the method described in the previous example,

4 chloro-19 nor testosterone was converted into 2-hy- By applying themethods of the previous examples to the 4-bromo-derivatives instead ofthe 4-chloro-derivae tives, there were obtained the correspondingZ-hydroxymethylene derivatives brominated at 0-4.

Example IV A solution of l g. of 2hydroxymethylene-4-chlorotestosteronein 20 cc. of water containing 600 mg. of sodium hydroxide was treateddropwise and under stirring with benzoyl chloride until the mixture hada weakly acidic reaction and while the temperature was maintained at C.The product was extracted with ether, washed with water to neutral,dried over anhydrous sodium sulfate, filtered and evaporated to dryness.Crystallization of the residue from acetone-hexane furnishedZ-benzoxymethylene-4-chloro-testosterone.

Example V A mixture of l g. of 2-hydroxymethylene-l7a-methyl-4-chloro-testosterone, 10 cc. of pyridine and 1 cc. of propionic'anhydride was kept over night at room temperature and then poured intowater and heated on the steam bath for half an hour. After cooling, theprecipitate was collected, washed with water and dried.Recrystallization from acetone-hexane produced2-propoxymethylene-17a-methyl-4-chloro-testosterone.

Example VI By substituting in the method of the previous example thepropionic anhydride for 1.1 molar equivalents of propionyl chloride,there was obtained the same compound.

Example VII A solution of 1 g. of 2-hydroxymethylene-4-chloro19-nortestosterone in 10 cc. of pyridine was treated with 1. cc. ofpropionic anhydride, in accordance with the method of Example V. Afterworking up the product as described in Example V, there was obtained thedipropionate of 2 hydroxymethylene 4 chloro-l9-nortestosterone, namelythe l7-propionate of 2-propionoxymethylene-4-chloro-19-nor-testosterone.

Example VIII A mixture of l g. of2-benzoxymethylene-4-chlorotestosterone, 10 cc. of pyridine and 1 cc. ofacetic anhydride was kept overnight at room temperature, poured intowater, heated on the steam bath for half an hour and cooled. Theprecipitate was filtered, washed with water, dried and recrystallizedfrom acetonehexane, thus yielding 2 benzoxymethylene 4chloro-testosterone 17- acetate.

Example IX Example X By the method to that of the previous example therewas prepared 2-ethoxymethylene 4 chloro-l9-nor-testosterone by reactionof 2-hydroxymethylene-4-chloro-19- nor-testosterone with ethyl iodide.

The treatment of the above Z-ethoxymethylene compound with propionicanhydride, in accordance with the procedure described in Example V, gave2-ethoxymethylene-4-chloro-19-nor-testosterone l7-propionate.

Example XI By substituting in the procedures of the previous Examples IVto X the respective testosterone derivatives chlorinated at C-4, bytheir 4-bromo derivatives, there were obtained the correspondingcompounds brominated at' C-4.

Example XII In the methods described in the previous examples, therewere substituted for the acid anhydrides or chlorides there mentioned,other derivatives of hydrocarbon carboxylic acids of less than 12 carbonatoms, which acid may be saturated or unsaturated, of straight orbranched chain, cyclic or mixed cyclic-aliphatic substituted or not withmethoxy, halogen or other groups; instead of the alkyl iodidesdescribed, we also used methyl iodide and benzyl iodide. There can thusbe prepared the corresponding monoesters formed by esterifying thehydroxyl group of the hydroxymethylene moiety of the 2-hydroxymethylene-4-halo-derivatives of testosterone, of 19-nor-testosterone and of the17a-alkyl analogs and 17ot-alkenyl analogs of such compounds; diestersof the 2-hydroxymethylene-4- halo-derivatives of testosterone and19-nor-testosterone, without substituent at C-17u, formed byesterification of the l7fi-hydroxyl groups and the hydroxyl group of thehydroxymethylene moiety, which diesters may be formed with the same ordifferent radicals; furthermore, there was prepared ethers obtained byetherification of the hydroxyl group of the hydroxymethylene moiety ofall of the 2- hydroxymethylene-4-halo-testosterones, substituted or notat C-17a, as well as 2-lower alkoxymethylene-4-haloderivatives and2-benzyloxymethylene 4 halo-derivatives of testosterones and19-nor-testosterones unsubstituted at C-17oc and esterfied at thesecondary hydroxyl group at C-17fi; the ester groups were specificallythe acetate, propionate, butrate, hemisuccinate, enanthate, caproate,benzoate, trimethylacetate, acetoxypropionate, cyclopentylpropionate,phenylpropionate or B-chloropropionate; the ether groups werespecifically methyl, ethyl, propyl and benzyl.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyland lower alkenyl, R is selected from the group consisting of hydrogen,lower alkyl, benzyl, and hydrocarbon carboxylic acyl of less than 12carbon atoms, R is hydrogen when R is other than hydrogen and R isselected from the group consisting of hydrogen and hydrocarboncarboxylic acyl of less than 12 carbon atoms when R is hydrogen, X isselected from the group consisting of hydrogen and methyl and Y isselected from the chlorine and bromine.

2. 2-hydroxymethylene-4-chloro A -androsten 17,6- ol-3-one.

3. The 17-monoesters of hydrocarbon carboxylic acids of less than 12carbon atoms of 2-hydroxymethylene 4- chloro-A -androsten-17j3-ol-3-one.

4. 2-hydroxymethylene 17a lower alkyl-4-chloro- A-androsten-l7fl-ol-3-one.

5. 2-hydroxymethylene-l7a lower alkenyl-4-chloro- A-androsten-17fi-ol-3-one.

6. 2-hydroxymethylene-4-bromo-A -androsten-17 8-01-3- one.

7. The 17-monoesters of hydrocarbon carboxylic acids of less than 12carbon atoms of 2-hydroxymethylene-4- bromo-A -androsten-17fi-ol-3-one.

8. 2-hydroxymethylene-17a-lower androsten-l7 3-ol-3-one.

9. 2-hydroxymethylene-l7a-lower alkenyl-4-bromo-Aandrosten-1713-ol-3-one.

alkyl-4-bromo-A 10. 2-hydroxymethylene-4-chloro-19-nor-A -androsten-17p-o1-3-one.

11. The 17-monoesters of hydrocarbon carboxylic acids of less than 12carbon atoms of 2-hydroxymethylene-4 chloro-19-nor-A -androsten-178-ol-3-one.

12. Z-hydroxymethylene-17a-lower a1ky1-4-ch1oro-19- nor-A-androsten-17B-ol-3-one.

13. 2-hydroxymethy1ene-17a-lower alkenyl-4-chloro-19- norA-androsten-17fl-o1-3-one.

14. Z-hydroxymethylene-4-bromo-19-nor-A -androsten- 17fl-o1-3-one.

15. The 17-monoesters of hydrocarbon carboxylic acids 6 of less than 12carbon atoms of 2-hydroxymethylene-4- bromo-19-nor-A-androsten-17fl-ol-3one.

16. Z-hydroxymethylene-17u-lower alkyl-4-bromo-19- nor-A -androsten-173-ol-3-one. 5 17. 2-hydroxymethylene-17a-lower alkenyl-4-bromo-l9-nor-M-androsten-l7fi-ol-3-one.

References Cited in the file of this patent Weisenborn et al.: J. Am.Chem. Soc., vol. 76 (Jan. 10 20, 1954) pages 552-555.

Camerino et 211.: I. Am. Chem. Soc., vol. 78 (July 20, 1956) pages 3540and 3541.

1. A COMPOUND OF THE FOLLOWING FORMULA: